The anthracycline antibiotic antibiotic adriamycin is of major clinical importance and is today the most widely used agent in cancer chemotherapy. A need exists, however to find analogs with improved therapeutic efficacy, extended spectrum of antitumor activity, or less toxicity. For some years these laboratories have been engaged in a broad program on the chemistry, biology, and pharmacology of anthracycline antibiotics and their semisynthetic analogs and derivatives. Among our accomplishments has been the synthesis, preclinical development, and clinical introduction of the novel adriamycin analog N-trifluoroacetyladriamycin-14-valerate (AD 32), an agent which is animal model systems shows therapeutic superiority to adriamycin and less toxicity, including significantly less cardiac toxicity. N-Trifluoroacetyladriamay cin-14-O-hemiadipate (AD 143) is currently being developed here as a second-generation AD 32 analog in an attempt to overcome the lack of water solubility of AD 32. A remarkable aspect of these analogs is that they do not bind to DNA, a property whch has generally been considered to be the mechanism of anthracycline aciton. In the present proposal we plan to systematically explore the structure-activity relationships of these and related non-DNA binding agents to be prepared here, including other water-soluble AD 32 analogs, in an attempt to find drugs with greater activity against anthracycline-resistant tumors. In addition, a variety of other C-9 acetyl side-chain modifications are proposed. The development of promising N-alkylated-14-O-acyl anthracyclines will continued. The synthesis and biological evaluation of various anthracycline analogs bearing fraudulent glycosidic moieties including axido- and amino-furanosides and azido-pyranosides, will be pursued as target compounds and as intermediates for the preparation of analogs containing active nitrosoureido-sugars. The synthetic conversion of so-called Class I anthracyclines into Class II-type and into analogs incorporating the molecular features of Class I and II structures is proposed. Potential routes to an improved synthesis of 14-[14C]-labeled anthracyclines will be tried. Target compounds will continue to be evaluated in a range of in vitro and in vivo bioassay systems for the development of structure-activity correlates and as a guide for future directions of this work.